CRISPR-Cas9 Used to Decelerate Aging Process in Mice with Hutchinson–Gilford Progeria Syndrome

Over time, cells start to lose functionality and their ability to repaired themselves and as functionality is lost and toxic proteins build up, age-related illnesses are to be expected. It may not be possible to prevent the development of age-released diseases, but it should be possible to delay the onset of those diseases by reducing some of the risk factors that lead to their development, ultimately increasing lifespans.

Researchers at the Salk Institute have used the gene editing tool, CRISPR-Cas9, to decelerate the aging process in mice by targeting one of the molecular drivers of aging.

The study was conducted on mice with progeria. Progeria is a rare autosomal dominant genetic disorder characterized by rapid aging. Typically, people born with the disorder only live to their early twenties. While there are several different forms of the disease, progeria is most often used to refer to Hutchinson–Gilford progeria syndrome (HGPS).

HGPS is caused by a mutation in the LMNA gene which leads to a buildup of the protein progerin inside cells. The LMNA gene produces two proteins inside cells associated with aging: Lamin A and progerin. The latter is a truncated and toxic version of lamin A which accumulates with age and more rapidly in individuals with HGPS. Currently there is no cure for the disease. Treatment involves managing complications as they arise.

“Progeria is an ideal aging model because it allows us to devise an intervention, refine it and test it again quickly,” said Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Laboratory and senior author of the paper.

The researchers hypothesized that disruption of the production of both lamin A and progerin could slow the aging process and potentially serve as a treatment for HGPS.

The CRISPR-Cas9 system was used to deliver the Cas9 enzyme inside cells of mice with progeria along with two gRNAs to guide the protein to the LMNA gene to perform an edit to prevent the production of lamin A and progerin. A reporter gene was also delivered to determine where the edits had been made. The cuts were performed in specific locations so as not to disrupt the production of lamin C. Cas9 was delivered using an adeno-associated virus (AAV).

Two months following treatment, mice with progeria were healthier, stronger, and more active and had improved cardiovascular health. Compared to the control group, there was decreased degeneration of an arterial blood vessel and the onset of bradycardia – Two characteristics of progeria and aging in general. Treated mice were as active as healthy mice of the same age and it was possible to increase the lifespan of the mice by around 25%

“Once we improve the efficiency of our viruses to infect a wide range of tissues, we are confident that we will be able to increase life span further,” explained Pradeep Reddy, co-author of the paper.

The research could, with some refinement, serve as a treatment for HGPS and other forms of progeria in humans.

The study is detailed in the paper – Single-dose CRISPR–Cas9 therapy extends lifespan of mice with Hutchinson–Gilford progeria syndrome – which was recently published in the journal Nature Medicine. DOI: 10.1038/s41591-019-0343-4